Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. While advances in complex molecule synthesis have illustrated that a remarkable range of structures can be prepared, the underlying difficulties of potential synthetic approaches often prevent interesting chemical structures from being selected for study. The underlying objective of this proposal is to provide fundamentally new entries to (i) simple chemical substructures that serve as subunits or precursors of many bioactive natural products and other complex structures, and (ii) complex carbohydrate- containing structures of the type that are well known to modulate the bioactivity of chemical entities, but that are often exceptionally challenging to prepare efficiently by existing methods. The first specific aim focuses on developing a mechanistically-driven approach for discovery of highly regioselective and enantioselective reductive coupling procedures. The expected impact of solving challenges in the regio- and enantioselective reductive union of aldehydes and alkynes will be the creation of a process that becomes widely adopted by synthetic chemists. This outcome will be broadly significant since allylic alcohols are an integral feature in many bioactive compounds and serve as versatile building blocks for a wide range of complexity-building and diastereoselective or enantioselective transformations. Furthermore, developing a fundamental understanding of the origin of regiocontrol in the catalytic operation will facilitate related advances in many other reactions that require regioselectivity in a catalytic insertion process. The second specific aim focuses on development of a suite of orthogonal catalytic processes for chemoselective glycosylation of complex molecules. The expected impact of our efforts to develop chemical methods for site-selective glycosylation will be that the speed, efficiency, and selectivity with which complex glycosylated structures may be obtained will be significantly improved. This outcome will allow the rapid preparation of either a specific target molecule or small collections of unnatural or natural product-derived glycosylated structures to examine as medicinal chemistry leads or probe molecules for biochemical studies. The approach represents a merger of two distinct fields: catalytic reductive coupling technology and carbohydrate chemistry, which have not previously been examined synergistically. This unique perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.